Project 3 of the Johns Hopkins Alzheimer?s Disease Research Center (JHADRC) is focused on the regulation of ?-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid receptors (AMPARs) by amyloid ? (A?) in order to identify mechanisms by which A? alters synaptic transmission and plasticity during the early stages of Alzheimer?s disease (AD) prior to cell death. AMPARs mediate the majority of fast excitatory neurotransmission in the central nervous system and are dynamically regulated by modifications such as phosphorylation and by interactions with other proteins. This regulation of AMPARs is critical for modulating synaptic transmission and plasticity. We propose that A? induces synaptic deficits by interfering with the normal regulation of AMPARs, resulting in down-regulation of AMPARs at excitatory synapses. Understanding this process is critical both for understanding early disease pathology and for generating effective therapies. Our project consists of the following three specific aims: (1) To test the hypothesis that elevated A? alters AMPAR phosphorylation to reduce surface AMPAR expression by altering interactions with proteins involved in receptor trafficking. This aim will allow us to identify cellular targets downstream of A? that may provide a mechanistic focus to directly slow or halt early progression of A?-mediated cognitive decline. (2) To use novel site-specific AMPAR phosphorylation mutant mice to determine the physiological and A?-mediated pathological role of phosphorylation in AMPAR trafficking, basal synaptic transmission, and synaptic plasticity. This aim will provide novel insight into the role of specific phosphorylation sites in different aspects of A?-induced synapse dysfunction. (3) To test the hypothesis that physiological and behavioral deficits induced by A? in vivo can be rescued with compensatory alterations in AMPAR modulation. In this aim we will take advantage of a transgenic mouse model of AD (APPswe/PS1dE9 mice) that more closely mimics the exposure of neurons to chronic, endogenously-produced A?, as occurs in AD patients. These mice will be used to determine if disruption of AMPAR phosphorylation or specific protein interactions can ameliorate deficits in synaptic plasticity and memory induced by chronic A? elevation. Through the studies in this proposal, we will identify mechanisms underlying A?-induced decreases in synaptic AMPAR expression and will determine if inhibition of these molecular changes is sufficient to rescue A?-induced deficits in synaptic transmission, synaptic plasticity, and memory.